The regulation of energy storage in man will be examined to ascertain those abnormalities which may be involved in the development and maintenance of human obesity. Obese, reduced-obese and never-obese (control) subjects will be studied under conditions which "stress" the regulatory systems contributing to weight homeostasis. Measures will be made at usually maintained weight as well as at higher and lower weight levels induced by over- and underfeeding. The overall efficiency of energy utilization will be determined by precise measure of the number of calories required to maintain constancy of body weight. Specific subcomponents of energy regulation (i.e., resting thermogenesis and the thermic effect of feeding) will be measured by indirect calorimetry using a constant flow hood with repeated, ultrasensitive measures of expired gas concentrations and flow rate. Biochemical analyses of adipose tissue obtained from various subcutaneous sites will be used to evaluate the characteristics of this tissue's response to catecholaminergic stimulation (Alpha 2 and Beta 1). Highly sensitive methods have been developed to measure both the sensitivity and responsivity of each of the modular components which link surface catecholaminergic receptors to the production of cAMP in this tissue. Finally, the systemic function of the autonomic nervous system will be monitored by a power spectrum analyses of heart rate variability which quantifies sympathetic and parasympathetic autonomic responses to food intake and adiposity. These measures will allow us to estimate the activity of major regulatory mechanisms involved in the homeostasis of caloric storage, and to isolate those abnormalities which may characterize the obese. The metabolic hazards which attend obesity are most likely associated with distortion of normal energy regulatory mechanisms in cardiovascular and other organ systems. These findings could have important implications with regard to therapeutic goals and the selection of modalities for the treatment of obesity.